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This dissertation, Control of Adenosine in Human Umbilical Vein Endothelial Cells During Inflammation by 李蕙琛, Wai-sum, Rachel, Li, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Control of adenosine in human umbilical vein endothelial cells during inflammation Submitted by Li Wai Sum Rachel for the degree of Master of Philosophy at The University of Hong Kong in August 2007 Inflammation of endothelium is closely related to the development of, and complications associated with atherosclerosis. Extracellular adenosine (ADO) levels are increased at the sites of inflammation. ADO is known to possess anti-inflammatory property so the increased ADO may protect tissues from inflammatory injury and potentially, slow down the development of atherosclerosis and adverse outcomes such as stroke and myocardial infraction. However, the mechanism(s) leading to the augmented extracellular ADO level during inflammation have not been fully understood. Based on the known mechanisms of endothelial ADO generation and removal, we suspected that three proteins in endothelial cells may be involved: 1) ecto-5'nucleotidase (E-5'Nu), which metabolizes extracellular adenosine monophosphate (AMP) into ADO; 2) 1 equilibrative nucleoside transporters (ENTs), which control the rate of ADO transport across cell membrane and 3) adenosine deaminase (ADA), which breaks down ADO into inosine (INO). The aim of this study is to explore the mechanisms by which ADO is increased during inflammation. The effects of pharmacological interventions of E-5'Nu, ENTs and ADA on inflammation were also examined. Moreover, the inhibitory effects of dihydropyridine-type calcium channel antagonists (DHPs) on ENTs and the contribution of this effect in reducing endothelial cell inflammation was also investigated. Stimulation of human umbilical vein endothelial cells (HUVEC) by lipopolysaccharides (LPS) was used as a model of endothelial inflammation. Our results showed that the activity and protein expression level of E-5'Nu in HUVEC were increased upon LPS stimulation at 24 hours but not earlier. The up-regulation of E-5'Nu was mediated through a phosphatidylinositol-3 kinase (PI3K)-dependent pathway. In contrast, the activity of ENTs and ADA in HUVEC were unchanged by LPS. Pharmacological inhibition of E-5'Nu increased the LPS-induced inflammation, as measured by the release of IL-8 from HUVEC, probably because the generation of ADO during inflammation was abolished. Inhibitions of ENTs and ADA reduced IL-8 release, probably because they potentiate the effect of ADO by retarding the cellular uptake and degradation of ADO. Interestingly, some DHPs inhibited ENT1 and 2 ENT2. This property might account for their anti-inflammatory effects on HUVEC. Our results suggest that some DHPs, while treating vascular disease such as hypertension and angina pectoris, may also have potential in suppressing endothelial cells inflammation and hence, atherosclerosis and its complications. (Word Count: 365) 3 DOI: 10.5353/th_b3955747 Subjects: EndotheliumAdenosineInflammationInflammation - Mediators

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